Stroke is the third leading cause of death in the United States, with ischemic strokes accounting for 83% of all strokes (Lloyd-Jones, D., et al., 2009. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 119, 480-6). Ischemic brain injury affects both white and gray matter. Although white matter integrity is essential to proper neuronal communication, much of current research is focused exclusively on neuronal damage. Accounting for 50% of brain volume in humans, white matter and the oligodendroglia that myelinate these areas play an integral role in proper brain function (Miller, A. K., et al., 1980. Variation with age in the volumes of grey and white matter in the cerebral hemispheres of man: measurements with an image analyser. Neuropathol Appl Neurobiol. 6, 119-32). The myelin produced by OLs not only supports axonal structural integrity, but is also essential in impulse integration (Baumann, N. and Pham-Dinh, D., 2001. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 81, 871-927). Thus, white matter protection is necessary to dampen stroke-induced injury and its progressive pathology (Arai, K. and Lo, E. H., 2009. Experimental models for analysis of oligodendrocyte pathophysiology in stroke. Exp Transl Stroke Med. 1, 6).
In addition to myelination, OLs support the survival and function of neurons by regulating axonal size and ion channel clustering. OLs also secrete trophic factors such as BDNF, NGF, GDNF and IGF-1, all of which aid in cell survival and maintenance (Baron-Van Evercooren, A., et al., 1991. Expression of IGF-I and insulin receptor genes in the rat central nervous system: a developmental, regional, and cellular analysis. J Neurosci Res. 28, 244-53; Kaplan, M. R., et al., 1997. Induction of sodium channel clustering by oligodendrocytes. Nature. 386, 724-8; Noble, M., et al., 2005 The Oligodendrocyte. Developmental Neurobiology, Vol., Plenum Publisher, New York; Wilkins, A., et al., 2003. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J. Neurosci. 23, 4967-74). Of the different types of glia, OLs are the most vulnerable to hypoxic and hypoglycemic conditions, yet the precise mechanisms underlying this susceptibility are unknown (Lyons, S. A. and Kettenmann, H., 1998. Oligodendrocytes and microglia are selectively vulnerable to combined hypoxia and hypoglycemia injury in vitro. J Cereb Blood Flow Metab. 18, 521-30).
HUCB cell therapy is an emerging treatment for CNS injury. The immaturity of HUCB cells contribute to the characteristic low immunogenicity (Sanberg, P. R., et al., 2005. Umbilical cord blood-derived stem cells and brain repair. Ann N Y Acad. Sci. 1049, 67-83). HUCB cells are less immunogenic than other stem cell treatments such as bone marrow and thus elicits lower immunomodulatory effects (Sanberg, P. R., et al., 2005. Umbilical cord blood-derived stem cells and brain repair. Ann N Y Acad. Sci. 1049, 67-83; Wang, M., et al., 2009. The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro. Immunology. 126, 220-32). In vivo, HUCB cells migrate to the site of injury, resulting in reduced infarct volumes, neuroprotection and preservation of white matter following MCAO (Hall, A. A., et al., 2009. Human umbilical cord blood cells directly suppress ischemic oligodendrocyte cell death. J Neurosci Res. 87, 333-41; Newcomb, J. D., et al., 2006. Timing of cord blood treatment after experimental stroke determines therapeutic efficacy. Cell Transplant. 15, 213-23; Newman, M. B., et al., 2005. Stroke-induced migration of human umbilical cord blood cells: time course and cytokines Stem Cells Dev. 14, 576-86; Vendrame, M., et al., 2004. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke. 35, 2390-5). Furthermore, multipotential stem cells derived from HUCB cells secrete neuroprotective, angiogenic and anti-inflammatory factors resulting in a functional recovery in spinal cord injuries (Chua, S. J., et al., 2010. The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Spine (Phila Pa. 1976). 35, 1520-6). In vitro experiments showed that in addition to growth factors, HUCB cells secrete cytokines, matrix metalloproteinase inhibitors, and interleukins (Neuhoff, S., et al., 2007. Proliferation, differentiation, and cytokine secretion of human umbilical cord blood-derived mononuclear cells in vitro. Exp Hematol. 35, 1119-31). Additionally, HUCB cells co-incubated with OLs reduced OGD-induced apoptosis by decreasing activated caspase 3 (Hall, A. A., et al., 2009. Human umbilical cord blood cells directly suppress ischemic oligodendrocyte cell death. J Neurosci Res. 87, 333-41). Despite these potent protective actions and known soluble factors, the precise pathways involved in HUCB cell-mediated OL survival have yet to be elucidated.
Therefore, what is needed is a method of targeting olidodendrocyte protection and repair during and after stroke and central nervous system infarct.